Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on celecoxib scaffold supported with in vivo anti-inflammatory activity, ulcerogenic liability, ADME profiling and docking study

Four new series of 1,2,4 triazole derivatives 4a,b 5a-d, 6a-f, and 7a,b possessing methylsulphonylphenyl moiety as COX-2 pharmacophore were designed and synthesized. The target compounds were prepared and evaluated in-vitro against COX-1 and COX-2 enzymes. Compounds 4a, 5b, 6a, and 7a showed the highest selectivity towards the COX-2 Enzyme (S.I. = 8.64-14.58) in comparison to celecoxib (S.I. = . 6.44). Interestingly, compounds 4a, 6a, and 7a showed good anti-inflammatory activity with edema inhibition (54.17, 53.03, and 50.29 %, in order) relative to the reference drug celecoxib (49.60%) after 3 h. Additionally, these potent derivatives 4a, 5b, 6a and 7a were significantly less ulcerogenic (U.I. = 2.27-2.97) than both reference drugs celecoxib (U.I. = 2.99) and indomethacin (U.I. = 20.25). Besides, a histopathological study of the stomach was also included. Moreover, docking simulation for the most selective compounds 4a, 5b, 6a, and 7a inside COX-2 active site was performed to explain their binding mode. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti-inflammatory agent. In conclusion, the above findings reveal that newly developed compounds 4a, 6a, and 7a represent a potential selective COX-2 NSAID candidate with minimum gastrointestinal risks.